Characterization of a novel covS SNP identified in Australian group A Streptococcus isolates derived from the M1UK lineage
ABSTRACT Group A Streptococcus (GAS) is a human-adapted pathogen responsible for a variety of diseases. The GAS M1UK lineage has contributed significantly to the recently reported increases in scarlet fever and invasive infections. However, the basis for its evolutionary success is not yet fully und...
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American Society for Microbiology
2025-02-01
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| Online Access: | https://journals.asm.org/doi/10.1128/mbio.03366-24 |
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| author | Johanna Richter Amanda J. Cork Yvette Ong Nadia Keller Andrew J. Hayes Mark A. Schembri Amy V. Jennison Mark R. Davies Kate Schroder Mark J. Walker Stephan Brouwer |
| author_facet | Johanna Richter Amanda J. Cork Yvette Ong Nadia Keller Andrew J. Hayes Mark A. Schembri Amy V. Jennison Mark R. Davies Kate Schroder Mark J. Walker Stephan Brouwer |
| author_sort | Johanna Richter |
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| description | ABSTRACT Group A Streptococcus (GAS) is a human-adapted pathogen responsible for a variety of diseases. The GAS M1UK lineage has contributed significantly to the recently reported increases in scarlet fever and invasive infections. However, the basis for its evolutionary success is not yet fully understood. During the transition to systemic disease, the M1 serotype is known to give rise to spontaneous mutations in the control of virulence two-component regulatory system (CovRS) that confer a fitness advantage during invasive infections. Mutations that inactivate CovS function result in the de-repression of key GAS virulence factors such as streptolysin O (SLO), a pore-forming toxin and major trigger of inflammasome/interleukin-1β-dependent inflammation. Conversely, expression of the streptococcal cysteine protease SpeB, which is required during initial stages of colonization and onset of invasive disease, is typically lost in such mutants. In this study, we identified and characterized a novel covS single nucleotide polymorphism detected in three separate invasive M1UK isolates. The resulting CovSAla318Val mutation caused a significant upregulation of SLO resulting in increased inflammasome activation in human THP-1 macrophages, indicating an enhanced inflammatory potential. Surprisingly, SpeB production was unaffected. Site-directed mutagenesis was performed to assess the impact of this mutation on virulence and global gene expression. We found that the CovSAla318Val mutation led to subtle, virulence-specific changes of the CovRS regulon compared to previously characterized covS mutations, highlighting an unappreciated level of complexity in CovRS-dependent gene regulation. Continued longitudinal surveillance is warranted to determine whether this novel covS mutation will expand in the M1UK lineage.IMPORTANCEThe M1UK lineage of GAS has contributed to a recent global upsurge in scarlet fever and invasive infections. Understanding how GAS can become more virulent is critical for infection control and identifying new treatment approaches. The two-component CovRS system, comprising the sensor kinase CovS and transcription factor CovR, is a central regulator of GAS virulence genes. In the M1 serotype, covRS mutations are associated with an invasive phenotype. Such mutations have not been fully characterized in the M1UK lineage. This study identified a novel covS mutation in invasive Australian M1UK isolates that resulted in a more nuanced virulence gene regulation compared to previously characterized covS mutations. A representative isolate displayed upregulated SLO production and triggered amplified interleukin-1β secretion in infected human macrophages, indicating an enhanced inflammatory potential. These findings underscore the need for comprehensive analyses of covRS mutants to fully elucidate their contribution to M1UK virulence and persistence. |
| format | Article |
| id | doaj-art-a8014e835c654758b70a3282d1209a92 |
| institution | Kabale University |
| issn | 2150-7511 |
| language | English |
| publishDate | 2025-02-01 |
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| spelling | doaj-art-a8014e835c654758b70a3282d1209a922025-02-05T14:00:48ZengAmerican Society for MicrobiologymBio2150-75112025-02-0116210.1128/mbio.03366-24Characterization of a novel covS SNP identified in Australian group A Streptococcus isolates derived from the M1UK lineageJohanna Richter0Amanda J. Cork1Yvette Ong2Nadia Keller3Andrew J. Hayes4Mark A. Schembri5Amy V. Jennison6Mark R. Davies7Kate Schroder8Mark J. Walker9Stephan Brouwer10Institute for Molecular Bioscience, Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, AustraliaInstitute for Molecular Bioscience, Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, AustraliaInstitute for Molecular Bioscience, Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, AustraliaInstitute for Molecular Bioscience, Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, AustraliaDepartment of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, AustraliaInstitute for Molecular Bioscience, Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, AustraliaPublic and Environmental Health, Pathology Queensland, Queensland Health, Coopers Plains, Queensland, AustraliaDepartment of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, AustraliaInstitute for Molecular Bioscience, Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland, AustraliaInstitute for Molecular Bioscience, Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, AustraliaInstitute for Molecular Bioscience, Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, AustraliaABSTRACT Group A Streptococcus (GAS) is a human-adapted pathogen responsible for a variety of diseases. The GAS M1UK lineage has contributed significantly to the recently reported increases in scarlet fever and invasive infections. However, the basis for its evolutionary success is not yet fully understood. During the transition to systemic disease, the M1 serotype is known to give rise to spontaneous mutations in the control of virulence two-component regulatory system (CovRS) that confer a fitness advantage during invasive infections. Mutations that inactivate CovS function result in the de-repression of key GAS virulence factors such as streptolysin O (SLO), a pore-forming toxin and major trigger of inflammasome/interleukin-1β-dependent inflammation. Conversely, expression of the streptococcal cysteine protease SpeB, which is required during initial stages of colonization and onset of invasive disease, is typically lost in such mutants. In this study, we identified and characterized a novel covS single nucleotide polymorphism detected in three separate invasive M1UK isolates. The resulting CovSAla318Val mutation caused a significant upregulation of SLO resulting in increased inflammasome activation in human THP-1 macrophages, indicating an enhanced inflammatory potential. Surprisingly, SpeB production was unaffected. Site-directed mutagenesis was performed to assess the impact of this mutation on virulence and global gene expression. We found that the CovSAla318Val mutation led to subtle, virulence-specific changes of the CovRS regulon compared to previously characterized covS mutations, highlighting an unappreciated level of complexity in CovRS-dependent gene regulation. Continued longitudinal surveillance is warranted to determine whether this novel covS mutation will expand in the M1UK lineage.IMPORTANCEThe M1UK lineage of GAS has contributed to a recent global upsurge in scarlet fever and invasive infections. Understanding how GAS can become more virulent is critical for infection control and identifying new treatment approaches. The two-component CovRS system, comprising the sensor kinase CovS and transcription factor CovR, is a central regulator of GAS virulence genes. In the M1 serotype, covRS mutations are associated with an invasive phenotype. Such mutations have not been fully characterized in the M1UK lineage. This study identified a novel covS mutation in invasive Australian M1UK isolates that resulted in a more nuanced virulence gene regulation compared to previously characterized covS mutations. A representative isolate displayed upregulated SLO production and triggered amplified interleukin-1β secretion in infected human macrophages, indicating an enhanced inflammatory potential. These findings underscore the need for comprehensive analyses of covRS mutants to fully elucidate their contribution to M1UK virulence and persistence.https://journals.asm.org/doi/10.1128/mbio.03366-24Streptococcus pyogenestwo-component systemCovRSSNPtranscriptional regulationSLO |
| spellingShingle | Johanna Richter Amanda J. Cork Yvette Ong Nadia Keller Andrew J. Hayes Mark A. Schembri Amy V. Jennison Mark R. Davies Kate Schroder Mark J. Walker Stephan Brouwer Characterization of a novel covS SNP identified in Australian group A Streptococcus isolates derived from the M1UK lineage mBio Streptococcus pyogenes two-component system CovRS SNP transcriptional regulation SLO |
| title | Characterization of a novel covS SNP identified in Australian group A Streptococcus isolates derived from the M1UK lineage |
| title_full | Characterization of a novel covS SNP identified in Australian group A Streptococcus isolates derived from the M1UK lineage |
| title_fullStr | Characterization of a novel covS SNP identified in Australian group A Streptococcus isolates derived from the M1UK lineage |
| title_full_unstemmed | Characterization of a novel covS SNP identified in Australian group A Streptococcus isolates derived from the M1UK lineage |
| title_short | Characterization of a novel covS SNP identified in Australian group A Streptococcus isolates derived from the M1UK lineage |
| title_sort | characterization of a novel covs snp identified in australian group a streptococcus isolates derived from the m1uk lineage |
| topic | Streptococcus pyogenes two-component system CovRS SNP transcriptional regulation SLO |
| url | https://journals.asm.org/doi/10.1128/mbio.03366-24 |
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